Principles of regulatory information conservation between mouse and human

Abstract

To broaden our understanding of the evolution of gene regulation mechanisms, we generated occupancy profiles for 34 orthologous transcription factors (TFs) in human–mouse erythroid progenitor, lymphoblast and embryonic stem-cell lines. By combining the genome-wide transcription factor occupancy repertoires, associated epigenetic signals, and co-association patterns, here we deduce several evolutionary principles of gene regulatory features operating since the mouse and human lineages diverged. The genomic distribution profiles, primary binding motifs, chromatin states, and DNA methylation preferences are well conserved for TF-occupied sequences. However, the extent to which orthologous DNA segments are bound by orthologous TFs varies both among TFs and with genomic location: binding at promoters is more highly conserved than binding at distal elements. Notably, occupancy-conserved TF-occupied sequences tend to be pleiotropic; they function in several tissues and also co-associate with many TFs. Single nucleotide variants at sites with potential regulatory functions are enriched in occupancy-conserved TF-occupied sequences. As part of the mouse ENCODE project, genome-wide transcription factor (TF) occupancy repertoires and co-association patterns in mice and humans are studied; many aspects are conserved but the extent to which orthologous DNA segments are bound by TFs in mice and humans varies both among TFs and genomic location, and TF-occupied sequences whose occupancy is conserved tend to be pleiotropic and enriched for single nucleotide variants with known regulatory potential. As part of the mouse ENCODE project Mike Snyder and colleagues studied the genome-wide transcription factor (TF) occupancy repertoires, associated epigenetic signals, and TF co-association patterns in mice and humans to broaden our understanding of the evolution of gene regulation mechanisms in mammals. The results indicate that although many aspects of TF occupied sequences are conserved in both species, the extent to which orthologous DNA segments are bound by orthologous TFs in human and mouse varies both among TFs and with genomic location. Importantly, TF occupied sequences with conserved occupancy tend to be pleiotropic; they are also enriched for single nucleotide variants (SNVs) that are known to have regulatory potential or are associated with known phenotypes.